Dual-pathway induction of pyroptosis

Pyroptosis, a highly pro-inflammatory form of immunogenic cell death, holds great promise for cancer treatment. However, its efficacy in cancer cells is often limited due to low efficiency and cellular complex pro-survival mechanisms. In this study, we address this challenge by an integrated nanoplatform simultaneously activating two pathways of pyroptosis. Manganese ions and imidazole serve as a framework to coordinate glucose oxidase (GOx) and epigallocatechin gallate (EGCG) into stable biomineralized-like nanoparticles. We hypothesize that EGCG, as an inhibitor of DNA methyltransferase, may restore the expression of Gasdermin E (GSDME), a crucial component of pyroptosis activated by cleaved caspase-3. Through glucose consumption, GOx triggers both the caspase-1/Gasdermin D (GSDMD)-mediated and caspase-3/GSDME-mediated pathways of pyroptosis simultaneously, leading to efficient pyroptosis in cancer cells and a robust anti-tumor immune response, accompanied by the upregulated expression of PD-L1. Our results reveal that integrating this strategy with immune checkpoint inhibitors results in a tumor inhibition rate exceeding 80% across several "cold" tumor models, a 20% cure rate in the CT26 unilateral tumor model, and 5/8 distant tumors remaining free of recurrence upon re-challenge. In conclusion, this dual-pathway induction of pyroptosis offers a novel and promising strategy for enhancing cancer immunotherapy.